The expression of transforming growth factor-betas (TGF-betas) was investigated in the skin of murine and human hosts with leprosy, using isoform-specific antibodies to TGF-beta1, -beta2 and -beta3 proteins. Different patterns of TGF-beta immunoreactivities were observed in human skin with lepromatous and tuberculoid leprosy. In lepromatous leprosy, macrophages containing several lepra bacilli (M. leprae) were immunostained with antibodies to mature TGF-beta1, anti-LC 1-30 and anti- CC 1-30, which react with intracellular and extracellular TGF-beta1, respectively; but there was no reactivity with anti-TGF-beta1 LAP protein. Macrophages without demonstrable intracellular M. leprae showed reactivity with TGF-beta1 LAP protein, but no reactivity with TGF-beta1 anti-LC and anti-CC. In the skin of patients with tuberculoid leprosy, giant cells and macrophages stained for TGF-beta1 LAP, but there was no immunostaining with TGF-beta1 anti-LC and anti-CC antibodies. Lepromatous granulomas in foot pads of mice showed a similar pattern of TGF-beta1 immunostaining to human lepromatous leprosy. Anti-TGF-beta2 and anti- TGF-beta3 immunostained giant cells and macrophages in tuberculoid leprosy, while macrophages in lepromatous leprosy were weakly stained. TGF-beta1 mRNA expression was reduced in cultured human monocytes challenged with irradiated whole M. leprae bacilli compared with untreated monocytes. These results suggest that the presence of bacilli in the activated macrophages could initiate proteolysis, which, in turn, might result in TGF-beta activation. The different patterns of expression of TGF-beta protein isoforms in the skin lesions and the reduced level of TGF-beta1 mRNA in human monocytes challenged with M. leprae may be significant in the immunopathogenesis of leprosy.